Metformin prevents the development of oral squamous cell carcinomas from carcinogen-induced premalignant lesions.

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a major public health concern. The recent identification of the mTOR complex 1 (mTORC1) signaling pathway as a highly prevalent molecular signature underlying HNSCC pathogenesis has provided the foundation to search for novel therapeutic approaches to prevent and treat HNSCC. Here, we asked whether metformin, the most widely used medication for the treatment of type II diabetes, which acts in part by stimulating the AMP-activated protein kinase (AMPK) signaling pathway thereby reducing mTORC1 activity, may lower the risk of HNSCC development. Indeed, we show that metformin reduces the growth of HNSCC cells and diminishes their mTORC1 activity by both AMPK-dependent and -independent mechanisms. We also optimized an oral-specific carcinogenesis mouse model that results in the accumulation of multiple oral premalignant lesions at the end of the carcinogen exposure, some of which then spontaneously progress into HNSCC. Using this mouse model, we observed that metformin specifically inhibits mTORC1 in the basal proliferating epithelial layer of oral premalignant lesions. Remarkably, metformin prevented the development of HNSCC by reducing significantly the size and number of carcinogen-induced oral tumoral lesions and by preventing their spontaneous conversion to squamous cell carcinomas. Collectively, our data underscore the potential clinical benefits of using metformin as a targeted chemopreventive agent in the control of HNSCC development and progression.

• Authors: Lynn Vitale-Cross, Alfredo A Molinolo, Daniel Martin, Rania H Younis, Takashi Maruyama, Vyomesh Patel, Wanjun Chen, Abraham Schneider, J Silvio Gutkind
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 5 Issue 4 Pg. 562-73 (Apr 2012) ISSN: 1940-6215 [Electronic] United States
• PMID: 22467081 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: 2012 AACR

Chemical References

• Anticarcinogenic Agents
• Carcinogens
• Hypoglycemic Agents
• Multiprotein Complexes
• Proteins
• Metformin
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Anticarcinogenic Agents (pharmacology)
• Carcinogens (toxicity)
• Carcinoma, Squamous Cell (prevention & control)
• Cell Line, Tumor
• Disease Progression
• Female
• Humans
• Hypoglycemic Agents (pharmacology)
• Mechanistic Target of Rapamycin Complex 1
• Metformin (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mouth Neoplasms (prevention & control)
• Multiprotein Complexes
• Precancerous Conditions (chemically induced)
• Proteins (metabolism)
• TOR Serine-Threonine Kinases